Edoxaban for stroke prevention in atrial fibrillation and factors associated with dosing: patient characteristics from the prospective observational ETNA-AF-China registry

Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA2DS2-VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose.


Methods
ETNA-AF-China (ClinicalTrials.gov:NCT04747496) is a multicentre, non-interventional, prospective, observational study conducted in 89 centres from four economic regions (East, Middle, West and Northeast as sequence of GDP from high to low) across Mainland of China (Fig. 1A; Table S1).This study use the method of economic region division in Mainland of China developed by National Bureau of Statistics of China under the policy of coordinated development, in which Bejing, Tianjing, Hebei, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Guangdong, Hainan consisting East; Shanxi, Anhui, Jiangxi, Henan, Hubei, Hunan consisting Middle; Inner Mongolia, Guangxi, Chongqing, Sichuan, Guizhou, Yunnan, Tibet, Shaanxi, Gansu, Qinghai, Ningxia, Xinjiang consisting West; Liaoning, Jilin, Heilongjiang consisting Northeast.
As part of the global initiative, comprising separate, non-interventional, prospective ETNA-AF registries in Europe, East Asia and Japan, ETNA-AF-China study is of similar design 22,23 .The study was approved by an institutional review board and Ethics Committee from Beijing Anzhen Hospital (No. 2019-058D), and all other clinical sites in compliance with the Declaration of Helsinki and Guidelines for Good Clinical Practice by International Conference for Harmonisation (ICH) and NMPA.All participants provided their written informed consent before participating in the study.
Eligible patients were unselected AF patients, treated with edoxaban at enrolment, and providing consent, and not simultaneously participating in any other interventional study.In the analysis, only patients treated with 60 mg or 30 mg OD edoxaban were included (Fig. 1B).

Baseline data collection
Baseline data were collected through an electronic subject case report form (eCRF), which recorded demographic information, vital signs, renal and hepatic parameters, medical history, types and symptoms of AF, previous/ concomitant medications, and administration status of edoxaban.The CHA 2 DS 2 -VASc and HAS-BLED scores were calculated based on the clinical characteristics.The values of creatinine clearance (CrCl) were calculated by the Cockcroft-Gault formula, and estimated glomerular filtration rate (eGFR) was normalized to 1.73 m 2 of body surface area (BSA) using Du Bois and Du Bois 24 .Renal impairment stage was classified based on eGFR range according to the KDIGO guideline 25 .Frailty and fall risk of each person were generally recorded by investigators' clinical judgement as the perceived aspect.The objective frailty was also determined using an adaptive modified frailty index (MFI) 26 , including the following variables: frequency of fatigue, dyspnea, or dizziness, history of diabetes mellitus (DM), Chronic obstructive pulmonary disease (COPD), Congestive heart failure (CHF), Myocardial infarction (MI), percutaneous coronary intervention (PCI), peripheral artery disease (PAD), transient ischaemic attack (TIA), or ischaemic stroke, and patients receiving treatment for hypertension.The

Statistical analysis
Continuous variables are presented as mean ± standard deviation (SD), whereas categorical variables are presented as frequencies and percentages (N [%]).To compare the distribution of patient parameters between groups, the Mann-Whitney U test for ordinal and continuous variables or the chi-squared test for categorical variables was used, wherever applicable.To identify factors associated with edoxaban non-recommended treatment under the known dose reduction criteria, a multivariable logistic regression analysis was performed by stepwise method entering variables with P < 0.05 at univariate logistic regression analysis (under reduced criteria).Odds ratios (ORs) with 95% confidence intervals (CIs) and P values for the effect of each variable on edoxaban treatment patient groups were estimated.Missing data were not computed.
All statistical analyses were performed using R Studio Statistical Software Version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria).A 2-sided P < 0.05 was considered statistically significant.

Characteristics of overall population enrolled
A total of 5001 patients were enrolled in ETNA-AF-China study between February 2021 and October 2022, of which 71 patients were excluded due to not meeting eligibility criteria, missing information on edoxaban treatment and receiving doses other than 60 mg or 30 mg, or at a frequency other than OD.Of 4930 patients included, the percentage of patients from economic regions of China were as follows: East (n = 2459 [49.9%]),Northeast (n = 426 [8.6%]), Middle (n = 1645 [33.4%]) and West (n = 400 [8.1%]) (Fig. 1A and B).
Overall, 6.4% (n = 316) of patients were perceived frail as assessed by the investigators, 5.6% were considered at risk of fall.The percentage of objective frailty according to the MFI score was 3.2% (n = 159).The most common comorbidity was hypertension (73.0%), followed by DM (26.2%), dyslipidaemia (24.9%), and heart failure (HF [14.4%]).History of ischaemic stroke, TIA, and ICH occurred in 7.2%, 2.2%, and 0.71% of patients, whereas 1.1% reported a history of major bleeding.At the time of enrolment, the first diagnosis of AF was made on average (± SD) over 4.5 years (54.8 ± 70.8 months) ago with 36.6% presenting with paroxysmal and 32.5% with persistent AF.A higher proportion of patients with AF concomitant or switched from the previously taken anticoagulants to edoxaban (Vitamin K antagonists [VKA]: 19.5%; other NOACs: 44.7%; Table 1).

Parameters associated with edoxaban dosing as label recommendation
To better understand the factors associated with edoxaban dosing prescription patterns by physicians, we analysed the clinical characteristics of enrolled patients with AF according to the label recommendation criteria using stepwise logistic regression models (Tables S3-S5).

Discussion
This report of baseline characteristics provides the first real-world data throughout Mainland of China of patients routinely treated with edoxaban as the largest, prospective, observational study on a single NOAC.Similar to the ETNA-AF study from other countries/regions, the results indicate patients were enrolled from all age groups, mainly older with mild renal impairment, and were characterised by moderate risk indicated by CHA 2 DS 2 -VASc score, history of CV diseases, stroke, bleeding events and concomitant use of antiplatelet agents, thereby complementing the data of the Phase III ENGAGE AF-TIMI 48 trial 10,28 .
Due to ethnic differences, patients with AF from East Asia, China, presented with distinct demographics, which will be translated into prescription patterns of NOACs in clinical practice.The ETNA-AF-China study is consistent with the XANAP study, regarding the characteristics of enrolled patients, such as the age, BMI, and CV comorbidities including hypertension and DM 29 .The average age of 70.2 years of Chinese patients treated with edoxaban is relatively younger compared with 73.3 years of those with rivaroxaban and 71.9 years with dabigatran in the Hong Kong Atrial Fibrillation Project, and older than the 67.2 years of patients from Mainland of China in the GLORIA-AF registry Phase II (post-approval of dabigatran) 30,31 .
In the ETNA-AF-China study, the mean calculated CHA 2 DS 2 -VASc (2.9) and the HAS-BLED scores (1.6) were lower than in other real-world observational or registry studies of NOACs for Asian patients (3.7 and ~ 2.0) 29,30 .This could be explained by the relatively lower rate of history of ischaemic stroke, TIA, and major bleeding events.
A recent population-based study demonstrated the common treatment changes of OAC in real-world practice 32 .Unlike the XANAP study and the GLORIA-AF registry, very few patients in the ETNA-AF-China study previously used VKA, whereas most of them switched from other NOACs 29,31 .As for Chinese AF patients, the still low use rate of OAC (about 30% of those with CHA 2 DS 2 -VASc score ≥ 1) and very low NOAC use (~ 0.5%) constituted the routine antithrombotic treatment, although improved over time 5,33,34 .The persistence rate of NOACs decreased to 81.3% at 3-year treatment among Chinese patients with AF 35 .Hence, the changes of previous OAC use in the ETNA-AF-China study could also be signified by the considerate long AF diagnosis duration (mean: 54.8 months, Q1-Q3: 4.3-76.5)and a large proportion of persistent (49.5%)AF.

Prescription patterns with recommended and non-recommended doses
In real-world practice, a total of 45.9% Chinese patients initially received the reduced dose of 30 mg, which is slightly lower than 50.4% in ETNA-AF-Japan but higher than the 23.4% proportion of patients in ETNA-AF-Europe 36,37 .For distribution of dose reduction criteria, ETNA-AF-China revealed that in evaluable patients who met the dose reduction criteria (including recommended and non-recommended doses), 81.4% (n = 1491/1832) had a body weight of ≤ 60 kg, 45.9% (n = 841/1832) presented a CrCl value of ≤ 50 mL/min, and 0.9% (n = 16/1832) were categorised with concomitant use of the label-listed P-gp inhibitor.Together with previous findings, these data show that edoxaban dosing in Asian patients was reduced more on body weight (Japan: 87.5%; Europe: 45.2%), while a larger percentage of patients in Europe received a reduced dose with low CrCl values (Japan: 49.6%; Europe: 84.9%).There was a good overall label adherence rate of 77.5% with edoxaban routine treatment.In ETNA-AF-China, non-recommended doses were prescribed in 22.5% of the patients, which matches the off-label dosing of NOACs in Europe (22%) but is lower than in Asia (32%) reported by an epidemiological meta-analysis, and greatly below the percentage of the non-recommended dose (> 80%) in the only 65 Chinese patient subgroup of the GARFIELD-AF study 7,21 .We found that 14.2% of patients received edoxaban non-recommended 30 mg instead of the recommended 60 mg called 'underdose' , and 8.3% of patients received non-recommended 60 mg instead of the recommended 30 mg called 'overdose' .Of note, the underdose rate of edoxaban in ETNA-AF-China was consistent with previous reported 12.6% in ETNA-AF-Japan, 19.1% in South Korean and Taiwanese patients, with the low overdose rates (2.3%, 10.1%) 56 .Our findings provide the overall prescription pattern of edoxaban to Chinese patients in real-world practice, complementing the data from global ETNA-AF programme.

Regional diversity of dosing recommendation
In ETNA-AF-China, the prevalence of dosing recommendations showed regional differences.The East region had the lowest percentage of non-recommended 30 mg (10.8%), compared to the West (16.8%),Middle (17.5%), and Northeast region (18.6%).According to the National Bureau of Statistics of China, the East region which accounted for 40% population contributed more than half of the Gross Domestic Product (GDP) as ~ 50-trillion-yuan in 2020, the Middle region contributing similar to that of West (~ 20-trillion-yuan), followed by the Northeast region (~ 5-trillion-yuan) 38 .The total number of tertiary and secondary hospitals (n = 5114), including certified stroke centres (≥ 10%) and registered medical doctors (3.6 million) was relatively high in the East and low in the Middle region (n = 4306, 2.3 million), while West region accounted for 4703 hospitals and 2.0 million registered doctors as obtained from the National Health Commision of China 39 .This high economic level and medical environment associated with the Healthcare Access and Quality (HAQ) index may explain the low probability of underdose NOAC use in East China.Further, we found that the majority of patients in the Northeast region were more likely to receive the recommended 60 mg, while a lowest percentage received non-recommended 60 mg.Epidemiological studies reported the geographical variance in the burden of stroke in China with the Northeastern region having the highest prevalence and incidence of stroke, the highest number of admitted strokes cases and the second highest mortality rate 3,6 .Considering the benefit of reduction in stroke/SEE events with 60 mg vs 30 mg edoxaban, physicians can carefully prescribe a high dose with label recommendation.

Characteristics and associated factors of NOACs dosing as label recommendation in AF patients
Adherence to OAC is influenced by patient preference, physician's clinical choice, and the healthcare system 40 .
Here, we identified several factors associated with non-recommended dosing, either for both doses or separately for 60 mg or 30 mg, in anticoagulated patients with AF.
Advanced age was a very strongly associated factor of both non-recommended doses and the 30 mg nonrecommended low dose.Our findings were in line with the previous studies, that advanced age as a category variable (≥ 75 years, ≥ 65 years) was a strong predictor of non-recommended low dosing of NOACs and as a continuous variable was independently associated with a non-recommended dose routinely used in rivaroxaban 20,21,41 .In real-world setting of Asian countries, low dose of edoxaban was commonly prescribed to older patients (age ≥ 75 years), 87.5% in the ETNA-AF-Japan study, 82.5% in the ANAFIE registry 36,42 .More than a leading factor for AF and related stroke, advanced age is associated with high levels of comorbidities and disability or frailty, emphasising the need of comprehensive consideration on the special patient group 43 .Some exploration on the association of frailty with dose recommendation has been made.The results demonstrated that the risk of falling is an independent factor for non-recommended dosing, and frailty is a strongly associated factor for non-recommended 30 mg.Consistently, more frail patients from the European countries were treated with edoxaban non-recommended doses, largely with the 30 mg non-recommended dose 26 .In a subgroup analysis of the ENGAGE AF-TIMI 48 trial, patients at a higher risk of falling or frailty experienced more events of major bleeding 44,45 .Data from the ANAFIE registry in older Japanese adults with AF add proof to the association between frailty and CV death, all-cause death and major bleeding 46 .Frailty was common in older patients and more likely accompanied with weight loss, risk of deterioration of renal function and presented as sarcopenia, leading to being bedridden or hospitalisation 47 .Patients with elevated frailty or falling risk received a non-recommended lower dose prescription likely in consideration of safety concerns.Since the increased frailty and risk of falling do not outweigh the benefits of NOAC treatment, precautions such as renal function monitoring and reduction of modifiable risk factors of bleeding assessment are advocated by the EHRA 48 .
History of HF was identified as an associated factor of non-recommended 30 mg.The real-world XANTUS study also reported the similar results that CHF was a predictor of non-recommended dosing 20 .Recently, HF was proven to be the prominent risk factor of all-cause death in AF patients and all-cause and CV death in NOAC users during a long term follow-up of 2 to 5.5 years 13,21,49 .This emphasises the importance of patient-centred as well as multidisciplinary comprehensive management including correct, persistent oral anticoagulation for patients coexisting with AF and HF, as the prevalence of HF in China is increasing within 5 years 50 .
In the current study, hypertension was associated with the 60 mg non-recommended dose.It has been recognised that hypertension contributed to the aetiology of AF and AF-related complications, such as stroke, bleeding risk, and HF 3,50 .Previously, hypertension (including treated with aldosterone antagonists) was identified as a predictor for either inappropriate overdose or underdose in the FANTASIIA and CODE-AF registries 41,51 .In ETNA-AF-China, we found that only a few patients (2.6%) had uncontrolled hypertension (systolic blood pressure [SBP] > 160 mmHg); Moreover, the average diastolic blood pressure (DBP) of non-recommended 60 mg was higher than the recommended 30 mg (76.1 vs. 74.3mmHg).Notably, a sub-analysis of the ENGAGE AF-TIMI www.nature.com/scientificreports/48 trial showed that patients with DBP of 75-85 mmHg have the most significant reduction in major bleeding on edoxaban treatment compared with a DBP 65-75 mmHg, implicating the pronounced safety profile 52 .We found that history of TIA was the strongest associated factor with non-recommended 60 mg, and the history of ischaemic stroke was associated with non-recommended 30 mg.Similarly, in the XANTUS study, patients taking the non-recommended dose of a NOAC were more likely to have a prior stroke/TIA 20 .In the GARFIELD-AF registry, a higher percentage of patients receiving non-recommended high dosing of NOACs had history of TIA, and more patients receiving non-recommended low dosing experienced previous stroke than those receiving recommended dosing 21 .The history of TIA or ischaemic stroke as strong predictors for recurrent stroke event has been demonstrated 13 .A stratification analysis of 1,141,097 patients with NVAF initiating oral anticoagulants showed that those at the second-high level of CHA 2 DS 2 -VASc score with a thromboembolic event history had a higher recurrent stroke incidence than those at the highest score level but without an event history, highlighting the independent influence by history of stroke 53 .Indeed, physicians may consider the predictive value of history of ischaemic stroke or TIA on the stroke risk assessment when prescribing, because the higher category of CHA 2 DS 2 -VASc score was associated with the mostly correct dose.Furthermore, patients with AF and a history of ischaemic stroke or TIA were at a higher risk of bleeding when receiving NOAC treatment, which indicated the safety profile consideration on 30 mg non-recommended doses for those patients 54,55 .
Female gender, concomitant antiplatelet use and DM were believed as the predictors of a non-recommended dose or low dose 20,21,41 .In line with the reported data, ETNA-AF-China revealed the association of female gender and antiplatelet use to non-recommended 30 mg prescription.Although dose reduction is recommended for edoxaban and rivaroxaban at CrCl ≤ 50 mL/min, patients with a CrCl value near the threshold were often prescribed a non-recommended dose.Our findings reinforced the understanding and attention to this patient group.

Non-recommended dosing and clinical implications
Although prescription pattern is well established in this study, optimal dosing for patients for the very elderly or high risk of bleeding remains a challenge for physicians.Globally, 'underdosed' edoxaban was reported to be associated with a higher risk of all-cause and CV death, while 'overdosed' had lower risk of ischaemic stroke without an increased risk of major bleeding 56 .In Asian patients with AF, several real world studies have found that non-recommended low dose NOACs are associated with reduced benefits, such as a higher risk of ischaemic stroke/SEE, and non-recommended high dose NOACs with similar risk of major bleeding 57,58 .In ETNA-AF-China, 435 patients with non-recommended 30 mg edoxaban in the ENGAGE AF-TIMI 48 trial met the eligibility criteria, the prescription of whom should be avoided.However, 166 (27.6%) patients were not included in the pivotal RCTs because they were older than 85 years, had a history of bleeding from critical organ or GI bleeding, concomitant use of NSAIDs, antiplatelets and 60 (10.0%) patients were considered frail.The ELDERCARE-AF trial showed that very low dose of edoxaban (15 mg OD) effectively prevented stroke or SEE, with no significant rising major bleeding risk in very elderly Asian patients with AF and high risk of bleeding 59 .From an Asian perspective, in patients with very advanced age, high bleeding risk or perceived frailty who did not meet the pivotal RCTs conclusion, flexible dosing could be considered based on shared physician judgement.Future studies on the ongoing ETNA-AF-China trial will assess the clinical impact of non-recommended edoxaban dosing for Chinese patients.

Limitations
Owing to the design of observational study, adherence of medication or receiving the prescribed dose could not be ensured, and treatment duration in different dosing groups were not compared.Approximately 14% (698/5001) of patients could not be characterised as recipients of recommended or non-recommended dosing, mainly due to missing CrCl values, and the values could not be retrieved due to the study's nature as a registry.Finally, like in all open-label studies, patients were aware about the treatment, and made decision to provide consent, which may have introduced some selection and ascertainment bias.

Conclusion
Edoxaban treatment in clinical practice in China was seen across all age groups and comorbidities, with a majority of patients being older than 65 years old with AF and having mild-to-moderate renal impairment.The adherence to label recommendation on dosing was high (77.5%),with slight regional variation.Advanced age was identified as the most relevant factor associated with non-recommended doses, with frailty having strongly association for the non-recommended 30 mg, and history of TIA for non-recommended 60 mg.These data demonstrate the baseline characteristics and prescription pattern of edoxaban in routine care in ETNA-AF-China and indicate the need for patient-centred, comorbidity management optimisation for improvement on future outcomes.

Figure 1 .
Figure 1.Overview of ETNA-AF-China study enrolment by (A) geographical distribution of centres, (B) flowchart.*A patient may fulfil one or more exclusion criteria; † Patients with one or more of the following clinical factors were dose reduced: moderate or severe renal impairment (creatinine clearance (CrCl) ≤ 50 mL/ min), body weight ≤ 60 kg or concomitant use of certain P-glycoprotein inhibitors listed in label and recorded at baseline.Not available category was considered on missing information for at least one potential dose reduction factor (i.e., renal impairment, body weight, P-glycoprotein inhibitors use), and no other reason fulfilled.CrCl, creatinine clearance; NVAF, nonvalvular atrial fibrillation.

Table 1 .
Baseline demographics and clinical characteristics for overall population included in ETNA-AF-China.